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History provided by the oncologist

Right neck mass since 2019; 04/07/20, initial biopsy p16-negative SCC, delay of treatment due to patient preference, agreed to biopsy of tonsil and work-up August 2022; right tonsil biopsy: p16-positive, G2 SCC, nodal mass at that time >6 cm with extensive extranodal extension, Stage III (cT2, cN3, cM0, p16-positive); based on this history, was staged as a tonsil primary and p16-positive.

Patient details

1. March 2020, CT neck and chest revealed a 0.5 x 2.7 x 2.3 cm low-density necrotic nodal mass at right neck level 2 suspicious for metastatic disease.  There was a slight asymmetric increased size of the right palatine tonsil.  There are a few sub-4 mm pulmonary nodules which are nonspecific.

2.  April 7, 2020, FNA of right neck mass with pathology revealed p16-negative SCC   

3.  April 20, 2020, PET/CT revealed 3 x 2 cm right-sided level 2 node with FDG avidity  

4.  May 5, 2020, flexible laryngoscopy showed no obvious primary lesion   

5.  May 2020, after evaluation by a medical oncology, patient declined any treatment  

6.  June 17, 2022, return visit in medical oncology after PET/CT demonstrates significant progression in the neck; patient definitively declines chemo, but would like surgical opinion.  Now has more rapidly progressive disease with skin breakdown and weeping from malignant lesion right neck.  

7.  June 22, 2022, radiation oncology consultation   

8.  July 15, 2022, tonsil biopsy: Invasive squamous cell carcinoma, moderately differentiated with LVI, p16-positive  

9.  Patient now agreeing to treatment with radiation: Tooth extractions 8/30/2022, radiation planning 9/14/2022  

10.  Patient consulted with cancer specialist who explained surgery is not recommended given level of extranodal extension and risk of seventh cranial nerve paralysis and fistula formation with surgical excision and who recommended chemoradiation

11.  September 9, 2022, patient presented for radiation CT simulation/treatment planning and informs treatment team. Patient declined/refuses concurrent chemotherapy despite recommendations from two cancer institutions.

Lung Rule M14 appears to be the first rule that applies to this case and instructs the user to abstract a single primary. However, we were hoping for confirmation that a cancer (NOS) or malignancy (NOS) would not be a distinctly different histology that may qualify for Lung Rule M8. Currently, these histologic terms are not included in the Table 3 options or mentioned in the preceding notes.

The patient was diagnosed with a biopsy-proven 12/2020 LUL SCC treated with radiation only, followed by a right hilar lymph node biopsy in 07/2022, that proved “metastatic pulmonary adenocarcinoma” per pathology and treated with radiation, followed by a biopsy-proven 12/2022 RLL SCC to be treated with immunotherapy only. The imaging never definitively identified a lung tumor that can be assumed to be a primary adenocarcinoma tumor.  In 06/2022, a PET scan only described a “strongly PET positive Rt inferior hilar LN vs infrahilar pulmonary mass,” as well as the subsequently biopsy-proven SCC in the RLL (12/2022 SCC primary). The biopsy path indicates this was a right hilar lymph node metastasis and does not indicate this is an infrahilar pulmonary mass. No other PET positive pulmonary lesions were seen at the time.

The oncologist’s assessment indicates the right hilar node was the only positive finding on the biopsy, and it was unclear if this right hilar node metastasis was from the left lung or if the primary was “not detectable.” The oncologist summarized this as a LUL lung lesion radiated for SCC, a right hilar lesion radiated for adenocarcinoma, and a RLL lung lesion on pathology found to be SCC.

Should the interval occurring metastatic adenocarcinoma be accessioned as a separate lung, NOS primary based on the histology difference? While the Solid Tumor Rules do not apply to metastasis, the oncologist did treat these three malignancies separately and does not indicate the hilar lymph node metastasis was felt to be from either SCC primary.

Acinar predominant adenocarcinoma measures at least 12 mm and involves wedge biopsy margins, while the lepidic predominant adenocarcinoma measures 11 mm and does not involve the margins of that separate specimen. Pathologist also notes, “CT findings of diffuse coarse reticular nodular opacity, these findings may represent pneumonic type adenocarcinoma/diffuse pulmonary involvement or intrapulmonary metastasis.  Both of these scenarios have the corresponding stages of pT4 (if thought to be ipsilateral) or M1a (if thought to also involve the contralateral lobe).”

Patient declined any further treatment and transitioned to hospice before expiring less than 1 month after wedge biopsies.

It is unclear if Rule M6 would apply to these two specimens with different subtypes since this scenario is not specifically addressed in the M rule definitions.

The patient was not synchronously diagnosed with multiple tumors, but three separate tumors with three different histologies were diagnosed at different times and no more specific histology was provided for the NSCLC. The timing rules do not apply to this case (the tumors were not greater than 3 years apart and they were not synchronously/simultaneously diagnosed).

While NSCLC is a NOS histology for both adenocarcinoma and squamous cell carcinoma, it is unclear if Rule M8 should apply because NSCLC is not listed in Table 3 (Table 3 is not an exhaustive list). In some situations, Rule M8 would apply if the tumors were different histologies and one of the histologies was not listed in the Table. Does that logic still apply if one of the tumors is NSCLC? If NSCLC is excluded from Rule M8, is Rule M14 the appropriate M Rule for the 2022 NSCLC diagnosis?

There was a 3.5 cm invasive adenocarcinoma tumor in the pancreatic head. There were four separate, sized pancreatic neuroendocrine tumors measuring 0.9, 0.7, 0.5 and 0.2 cm in the pancreatic body. There are multiple tumors with distinctly different histologies. However, Table 11 (Pancreas Histologies) does not include any entries for neuroendocrine tumors of the pancreas (e.g., pancreatic NET, WHO grade 1, histology 8240). While it would seem Rule M19 should apply as they’re distinctly different histologies, because PanNETs are not included in Table 11, it is not clear which M Rule applies to these multiple tumors.

If Rule M19 does not apply, we are left with Rule M21 (Abstract a single primary when there are multiple tumors that do not meet any of the above criteria). Are these separate tumors with distinctly different histologies really a single primary? Pancreatic neuroendocrine tumors are not an uncommon histology, is there a reason these were not included in Table 11?

Since the peripheral nerves are included in the Malignant CNS schema of the Solid Tumor Rules, neither the differences in subsite nor timing indicate these are separate primaries (Rule M10 indicates a single primary). However, these are separate MPNSTs in different sites and the tumors are not stated to be metastasis. Additionally, these are treated as separate primaries by the managing physician.

While the malignant CNS tumors do not take timing into account, is this correct for these peripheral nerve tumors that are often treated similarly to soft tissue tumors? Should Rule M8 be updated to include tumors in different peripheral nerve subsites?

SINQs 20190083, 20180088, and 20130221 all indicate diagnoses of prostate adenocarcinoma, followed by a diagnosis of metastatic small cell carcinoma of the prostate are separate primaries because these are distinctly different histologies. Does this logic still apply for 2023 and later since Rule M4 was added to the Other Sites M Rules? Rule M4 states, “Abstract multiple primaries when the patient has a subsequent small cell carcinoma of the prostate more than 1 year following a diagnosis of acinar adenocarcinoma and/or subtype/variant of acinar adenocarcinoma of prostate.”

This patient has a 2018 diagnosis of prostate adenocarcinoma treated with radical prostatectomy, followed by a 2023 diagnosis of metastatic small cell carcinoma of the prostate diagnosed on a liver metastasis core biopsy. Rule M4 does not indicate whether it applies to subsequent biopsy confirmed metastatic tumor only. When a diagnosis of small cell carcinoma follows a diagnosis of prostatic adenocarcinoma, it is almost always confirmed in metastatic sites rather than in the primary site. Does the logic in the referenced SINQs above still apply for Rule M4?

Rule M4 was added to the Other Sites M Rules to address diagnoses of small cell carcinoma following prostate adenocarcinoma, but Rule M4 states the diagnoses must be greater than one year apart.

In this situation, the diagnoses were less than one year apart and one must continue through the M Rules. The next M Rule that applies Rule M19: “Abstract multiple primaries when separate/non-contiguous tumors are on multiple rows in Table 2-21 in the Equivalent Terms and Definitions. Timing is irrelevant.” If one were to STOP at the first rule that applies, one would stop at Rule M19 which confirms the prostatic adenocarcinoma and small cell carcinoma are separate primaries, regardless of timing. If these are not to be accessioned as multiple primaries, does an Exception need to be added to M19?

Example:  A prostate core biopsy showed intraductal carcinoma in 09/2022, which is an in situ tumor.  A core biopsy again showed intraductal carcinoma in 12/2022.  The subsequent radical prostatectomy in 04/2023, revealed multiple foci of invasive prostate adenocarcinoma with extensive intraductal carcinoma. 

Per Solid Tumor Rules, Other Sites, Rule M3, acinar adenocarcinoma of the prostate is always a single primary.  Note 4, this rule applies to subtype variants of acinar adenocarcinoma listed in Table 3, which has intraductal/ductal as a variant subtype of acinar adenocarcinoma. Does rule M3 apply to incidence cases (an invasive tumor following an in situ tumor)?